Pain imposes a tremendous burden on society, costing approximately US$1 trillion per year in medical treatment, loss of productivity and disability payments in developed countries, not to mention the human suffering associated with moderate to severe acute and chronic pain. Current treatments are insufficient to address the challenge of acute and chronic pain. Narcotics pose a problem of addiction and safety risk while other types of analgesics (e.g. NSAIDs, COX2 inhibitors, antidepressants and anti-epileptics) are hampered by limited efficacy and acute or long-term side effects. Moreover, the recognition of the progressive nature of pain, with pain evolving into persistent allodynia and hyperalgesia due to the presence of chronic disease (e.g. inflammation) and plasticity of neuronal mechanisms involved in pain, calls for the development of novel analgesic treatments with disease modifying potential. Future therapies should address pain transmission (analgesic activity) while ameliorating the cause of pain (e.g. inflammation) and reversing the abnormal neuronal changes causing allodynia and hyperalgesia. The recent discovery that lipid-mediators called resolvins, activate ChemR23 G-protein coupled receptors to induce analgesia, ameliorate inflammation, and reverse neuronal plasticity associated with chronic pain presents a unique opportunity to develop therapies with transformational potential. We propose an innovative approach to identify novel ChemR23 small molecule agonists by using new functional screening technologies based on label free formats, and signal transduction analysis to select and optimize molecules with optimal pharmacological profiles. Given the clinical validation of resolvins as anti-inflammatory ligands and the correlation of ChemR23 mechanisms of analgesia with processes of clinical relevance, ChemR23 agonists may represent a novel new class of analgesics to treat acute and chronic pain conditions. PUBLIC HEALTH RELEVANCE: There is a critical medical need to develop novel treatments for pain that are safe and induce effective analgesia while reversing the pathology causing hyperalgesia and allodynia. This proposal details a new approach to develop novel pain treatments based on a new mechanism of action that has the potential to induce analgesia, ameliorate inflammation and reverse neuronal alterations that lead to and sustain chronic pain. Drug products developed in this program could be transformative in pain management with the potential of disease modifying actions in chronic pain.